Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer

Abstract

BackgroundNo previous study has addressed the efficacy of NF-κB blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κB activation and therapeutic impact of NF-κB blockade by the novel NF-κB inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells.MethodsTwo human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro.ResultsIntranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively.ConclusionThere was a distinct change in the activation level of NF-κB between T24 and T24PR cells, suggesting strong nuclear localization of NF-κB could be a promising target after developing acquired platinum-resistance in bladder cancer.

Personalized disease signatures through information-theoretic compaction of big cancer data

“…Therefore, two patients can display similar gene expression levels, but their tumors may harbor different combinations of unbalanced processes. To demonstrate this point, we selected two bladder cancer patients, indexed 164 and 172, and inspected their tumor-specific experimental expression levels of five bladder cancer-associated genes: NF-κBIA (the inhibitor of NF-κB) (28,29), PD-L1 (30), CD44 (31), EGFR (32), and PLAU (33) (Fig. 3A).…”

Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer

“…NF-κB activation has been implicated in acquisition of CDDP resistance [26, 27]. We therefore investigated whether androgens/AR regulate the expression and activity of NF-κB in bladder cancer cells.…”

Mining for Candidate Genes Related to Pancreatic Cancer Using Protein-Protein Interactions and a Shortest Path Approach

“…Targeted by a specific microRNA, miR196a, NFKBIA has been proved to be associated with PC, especially in the metastasis process [ 31 ]. As we have mentioned above, in most tumors including pancreatic cancer, NF-kappa-B pathway has been widely reported to be overactivated and has a close connection with the patients' prognosis, indicating the underlying relationship between NFKBIA and the pancreatic cancer [ 34 – 37 ]. Mutations have been widely reported to contribute to specific functional alteration of crucial proteins including NFKBIA in diseases especially in various cancer subtypes like pancreatic cancer [ 38 – 41 ].…”